Elevated expression of erbB3 receptor correlates with increased distant metastasis of breast cancers with amplification and/or overexpression of erbB2 (HER2/neu), which occur in approximately 25-30% of invasive breast cancers and are significantly associated with a worse prognosis in breast cancer patients. The erbB3 receptor frequently co-expresses and interacts with erbB2 in breast cancer to activate the oncogenic signaling, especially the PI-3K/Akt pathway and Src kinase. ErbB3 serves as a co-receptor of erbB2 and plays a critical role in the development of erbB2-overexpressing (erbB2+) breast cancer. Our recent data reveal that overexpression of erbB3 decreases, and inhibition of erbB3 signaling with an erbB3 specific shRNA, an anti-erbB3 blocking antibody (Ab), or an Akt inhibitor increases the levels of miR-203 and miR- 542-3p in erbB2+ breast cancer cells. Interestingly, both miR-203 and miR-542-3p have been identified as tumor suppressive miRNAs, and are frequently downregulated due to promoter methylation in various human cancers, including breast cancer. Bioinformatics analysis suggests that miR-203 and/or miR-542-3p target several critical genes, including Survivin, ZEB1, ZEB2, Snail1, and/or Slug, responsible for drug resistance, epithelial-mesenchymal transition (EMT), and tumor metastasis. We also discover an enhanced expression of ZEB1, Snail1, Slug, and Vimentin upon ectopic expression of erbB3 in erbB2+ breast cancer cells. Thus, we hypothesize that activation of erbB3 signaling promotes erbB2+ breast cancer metastasis via epigenetic silencing of the tumor suppressive miR-203/miR-542-3p and effective inhibition of erbB3 will significantly suppress metastasis via induction of miR-203/miR-542-3p. We intend to define miR- 203 and miR-542-3p as the key downstream mediators of erbB3 signaling to enhance metastatic potential of erbB2+ breast cancer cells by upregulating the EMT markers; and identify novel strategy/agents inhibiting erbB3 to prevent or attenuate erbB2+ breast cancer metastasis via induction of miR-203/miR-542-3p.